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furo[3,2-g] chromen Derivatives as a Novel Series of Estrogen Receptor Modulators

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furo[3,2-g] chromen Derivatives as a Novel Series of Estrogen Receptor Modulators

    furo[3,2-g] chromen Derivatives as a Novel

    Series of Estrogen Receptor ModulatorsCHEM.RES.CH1NESEUNIVERSITIES2011,27(1),54—59

    Design,SynthesisandBiologicalEvaluationof

    2-Aroyl3aryl6,7dihydro5H-furo[3,2-g]chromen

    DerivativesasaNovelSeriesofEstrogen

    ReceptorModulators

    ?NGShi.hui,,ANGYan,ZHUYu.ying,LIUSi-jie,HANJianZHOUYi.fan,

    LIDa.wei.KOIRALADiwaandHUChun

    .

    KeyLaboratoryofStructure—basedDrugDes@n&Discovery,MinistryofEducation.DepartmentofOrganicChemistry,SchoolofPharmaceuticalEngineering,ShenyangPharmaceuticalUniversity,Shenyang110016,R.China,

    2.SchoolofPharmacy,ShanghaiJiaotongUniversiShanghai200193,R.China

    AbstractBasedontheprinciplesofthebioisosterism,combinationoftheactivesubstructuresofselectiveestrogen

    receptormodulatorswhicharecurrentlytherapeuticagentsavailableforthepreventionandtreatmentofvariouses.

    trogendependentdiseases,andstructuraloptimization,anovelseriesof2-aroyl-3aryl

    一羽一6,7-dihydro-5H-furo[3,2

    chromenderivativeswasdesignedaspotentselectiveestrogenreceptormodulatorsviamoleculardocking.Thetarget

    compoundshavebeensynthesized,andcharacterizedbvIR,protonNMR,ESI-MSelementalanalysisandevaluated

    f0rtheirantitumoractivityagainsthumanosteosarcomaU2OS.EGFP.4F12Gcellline.Sometargetcompounds

showedgoodinhibitioneffectsonU2OS.EGFP.4F12Geelllineandthepreliminarystructure

    .activityrelationships

    werediscussed.

    KeywordsSelectiveestrogenreceptormodulator;Docking;Biologicalactivity;Heterocycl

    e;Furo[3,2-g]chromen

    ArticleIDl005.9040(2011,.01.054—06

    1Introduction

    Theestrogenreceptor(ER)isaligandactivatedtranscrip-tionfactorwhichplaysanimportantrolenotonlyintheregula—tionofthefemalereproductivesystem.butalsoinbone.cardi.ovascularandcentralnervoussystemfunctionL".Selectiveestrogenreceptormodulators(SERMs),whichactasERago—nistsinsometissueswhileactingasERantagonistsinothers.arccurrentlyavailableforthetreatmentofvariousestrogendependentdiseasessuchasbreastcancer,osteoporosis.Alz.heimer,sdisease.andcoronaryheartdisease[2--4].ThecurrentlyapprovedSERIVESaretamoxifenandtoremifeneforthetreat.mentofbreastcancerandraloxifeneforthetreatmentofos-teoporosis(Fig.1).HoweveLthesedrugsoftencauseseveralundesirablesideeriectssuchasincreasedincidenceofendo.metrialcancerandhotflashesl5,61.whichstimulatesourinterestinfindingmoreeriectiveSER1~4s.

    o.

    ?

    .H

    Itisknownthatfurochromenringisaninterestingstruc—tureforitsvariousbiologicalactivitiesincludingantitumorIandantiviraltactivity.

    一鲥Itwasconceivedthatfurod,2.

    c~omenscaffold.whichresembleswiththecoreofbenzothi.opheneinraloxifene.wouldinteractwithERandmayprovide

    estrogenicligandsofinterest.Theamine.containingsidechainoftheseSERMsisrecognizedtobecriticalinbindingtotheaminoacidresidueoftheER,andalsoplaysaroleindeter—miningthetissuespecificityt1.

    InordertodiscoversomenovelSERMswithDovel

    scaffolds.basedonthcprinciplesofbioisosterism,combinationoftheactivesubstructuresoftamoxifen.toremifeneandralo-xifene.andstructuraloptimization.aDovelseriesof

    2-aroyl-3aryl6,7-dihydro?5H-furo[3,2g]chromenderivatives

    Correspondingauthor.E—mail:chunhu@syphu.edu.cnReceivedApril2,2010;acceptedJune6,2010.

    SupportedbytheNationalNaturalScienceFoundationofChina(No.20474053)

    No.1WANGShi.huietal

    wasdesignedwithmoleculardockingprogramandsynthe—sized.

    2Experimental

    2.1MaterialsandApparatuses

    Allthereagentswereofanalyticalreagentgrade.Themeltingpointwasdeterminedonopencapillarytubesandthethermometerwasuncorrected.InflaredspectrawererecordedonaBruker$55spectrometerviaKBrpelletsProtonNMRspectrumwasmeasuredonaBrukerspec?trometeroperatedat300MHzor600MHzwithCDClorDMSO.dasthesolventandTMSastheinternalstandard.Massspectrawasrecordedonaelectrosprayion(ESI)sourceinaWlatersspectrometerat3.5kVsprayvoltage.ElementalanalysiswascarriedoutonaPerkin-Elmer2400elementalanalyzer.

    2.2Synthesis

    2.2.1Synthesisof7-Hydroxy4chromone1)

    Toasolutionof2,4dihydroxyacetophenone(15.2g,100

    mmo1)andethy1orthoformate(83mL,500mmo1)wasadded70%perchloricacid(10mL.12Ommo1).Themixturewasstirredatroomtemperatureforlhandpouredto200mLofethylether,subsequently,theslurrywasfilteredandthesolidwaswashedwithcoldwaterandrecrystallizedfromethano1togivecompound1asawhitesolid,yield85.4%,m.P.214—

    215.C(Lit.":215—216.C,.

    2.2.2Synthesisof7-Hydroxychroman(2)

    Around.bottomedflask(250mL1waschargedwithcom.pound1(7.60g,50mmo1),10%palladiumovercharcoal(0.05g,5mrno1)andethanol(100mL)inhydrogengas,andthemixturewasrefluxedfor4h.Uponcooling.themixturewasfiltered.Thefiltratewasconcentratedtodrynessandtheresiduewasrecrystallizedfromethanoltogivecompound2asawhitesolid,yield95.0%.m.P.87—89.C(Lit.L:9l.C,.

    2.23Synthesisof7(4-Methoxybenzoyloxy)chro—

    man(3)

    Toasolutionofcompound2(40mmol1andtriethyla.mine(44mmol1in80mLofdichloromethanewasadded4-methoxybenzoylchloride(44retoo1).Themixturewasstirredatroomtemperaturefor3handmonitoredbyTLC.111emix—turewaswashedwithdilutedhydrochloricacid(1mol/L,andwater(20mLx3),andthecombinedorganiclayerwasdriedoverMgSO4.Afterdistillationunderreducedpressure,there-siduewasrecrystallizedfromethano1.Thiscompoundwasobtainedasawhitecrystal,yield90.6%,m.P.92—94.C;HNMR(300MHz,CDC13),:1.97—2.05(m,2H,CH2),2.79(t,2H,CH2),3.89(s,3H,OCH3),4.18(t,2H,CH2—0),6.64(d,1H,Ar—H,2.1Hz),6.66—6.70(dd,1H,Ar_H,J=-8.2,2.1Uz),

    卜一6.97(d,2H,AH,J--8.8Hz),7.05(d,1H,Ar—H,J=8.2Hz),

    8.14(d,2H,Ar—H,J=8.8Hz);ESI-MS,m/z:285.1[M+H.

    2.2.4Synthesis0j6(4Methoxybenzoy1)7hydro—

    xvchroman(4)

    Amixtureofcompound3(30mmo1)andstannicchloridef150mmo1)washeatedunderrefluxfor8h.Thesolutionwaspouredtoicewaterandtheprecipitationappeared,thesolidwaswashedwithcoldwaterandrecrystallizedfromethano1.Thiscompoundwasobtainedasawhitecrysta1.yield80.4%.m.P.148—150.C:HNMR(600MHz,CDCl),:1.99—

    2.01(m,2H,CH2),2.68(t,2H,CH2),3.90(s,3H,OCH3),4.24(t,

    卜一2H,CH2—0),6.43(s,1H,H),6.99(d,2H,AH,J=9.0

    Hz),7.30(s,1H,Ar—H),7.65—7.66(dd,2H,A_H,J=9.0,2.4

    Hz),12.24(s,IH,oH);ESI-MS,m/z:285.1M+Hr.

    2.2.5Synthesisof2-Aroyl-3f4methoxypheny1)6.7

    一由dihydro5H-furo[3.2chromen(5)

    Amixtureofcompound4(20mmo1),substitutedphenacylchloride(20mmo1),tetrabutylammoniumbromide(10mmo1),30mLof30%aqueouspotassiumcarbonateand70mLofdichloromethanewasrefluxedfor12h.Themixturewaswashedwithdilutedhydrochloricacid(1mol/L)andwater(20mL~3),andthecombinedorganiclayerwasdriedoverMgSO4.Afterdistillationunderreducedpressure,theresiduewasrecrystallizedfromethano1.

    2-Benzoyl-3-(4-methoxypheny1)6,7-dihydro-5H-furo[3,2

    g]chromen(Sa)wasobtainedasayellowcrystal,yield73.7%,m.P.107—109.c;IR(KBr),aT/cm:2933,1628,155l,l506,1334,13l1,1290,1251,1152,l127,1002,829,719,695;'HNMR(600MHz,CDC13),:2.04—2.06(m,2H,CH2),2.910,2H,CH2),3.83(s,3H,OCH3),4.27(t,2H,CH2—0),6.89—

    6.91(dd,2H,H,J=6.6,1.8Hz),7.01(s,1H,Ar—H),

    7_3l7.35(m,3H,Ar—H),7.41—7.47(m,3H,Ar—H),

    7.83—7.85(dd,2H,A_H,J=8.4,1.2Hz).ESI—MS,m/z:

    】十385.2M+H,407.2[M+Na],423.1M+K+.

    2-(4-ChIorobenzoyI)-3(4methoxyphenyI)6,7dihydro-

    5H-furo[3,2-g]chromen(5b)wasobtainedasayellowcrystal,yield80.2%,m.P.136—138.C;IR(KBr),/cm:2957,1638,1589,1563,l5071490.13481284,l255,l162.11241026,843,790,622;HNMR(600MHz,CDCl3),:2.04—2.06(m,2H,CH2),2.91(t,2H,CH2),3.84(s,3H,OCH3),4.27(t,2H,

    cH2—0),6.92(d,2H,H,J--8.4Hz),7.O0(s,IH,H),

    卜一7_31—7.32(m,3H,AH),7.41(d,2H,AH,J=9.0Hz),

    】十7.80(d,2H,AI—-H,.]--8.4Hz).ESI-MS,m/z:419.2M+H,

    441.2[M+Na],457.1M+K1.

    2-(4Methylbenz0y1)3(4-methoxypheny1)-6,7-dihydro-

    5H-furo[3,2g]chromen(Sc)wasobtainedasayellowcrystal,

    yield72.2%,m.P.113l15.C:IR(KBr),17/cm_1:29331640,1606,1555,1506,1334,1291,1250,l176,l152,1126,1003,83l,773,761;HNMR(600MHz,CDC13),:2.04—2.06(m,2H,CH2),2.38(s,3H,CH3),2.91(L2H,CH2),3.83(s,3H,OCH3),4.26(t,2H,CH2—0),6.91—6.92(dd,2H,Ar—H,J=-6.6,1.8Hz),7.00(s,IH,Ar—H),7.16(d,2H,Ar—H,J=-7.8Hz),7.3l(s,IH,Ar—H),7.44—7.45(dd,2H,Ar—H,J=6.6,1.8

    卜一Hz),7.79(d,2H,AH,J=8.4Hz).ESI.MS,m/z:399.2

    [M+Hr.

    2.2.6Synthesisof2-Aroyl3f4hydroxypheny1)6.7

    一曲dihydro5H-furo[3.2chromen(6)

    Borontribromide(10mmo1)wasaddedtoadryCH,C1,(30

    mL)solutionofcompoundS(5mmo1)at15.Cbydropping.

    Themixturewasstirredat-15.Cfor4handmonitoredbyTLC.Thesolutionwaspouredtowater,theresultingmixture56CHEM.RES.CHINESEUNIVERSITIESVO1.27

    wasextractedwithCH2C12(20mE),andtheorganicphasewaswashedwithwaterandthendriedoveranhydrousMgSO4.

    Afterdistillationunderreducedpressure,theresiduewasre—crystallizedfromethano1.

    2-Benzoyl3-(4hydroxypheny1)6,7dihydro5H-furo[3,2

    g]chromen(6a)wasobtainedasayellowcrystal,yield73.7%,m.P.214—216.C;IR(KBr),P/cm:2933,l625,l591,1547,1509,1334,13l0,1244,l153,l128,1126,1003,988,837,

    725;HNMR(300MHz,DMS0d6),:1.961.99(m,2H,

    CH2),2.90(t,2H,CH2),4.23(t,2H,CH2—0),6.74(d,2H,

    H,J=8.4rtz),7.00(s,lH,Ar—H),7.27(d,2H,Ar—H,J--8.4Hz),7.34—7.41(m,3H,Ar—H),7.50—7.52(m,2H,

    H),7.71—7.74(dd,2H,Ar—H,J=8.4,1.5Hz).ESI-MS,

    m/z:371.2[M+HI,393:2[M+Na],409.1M+K+.Elemental

    ana1.(%)caled.forC24H1804:C77.82,H4.90;found:C77.7l,H4.85.

    2-(4-Chl0robenzoy1)3-(4hydroxypheny1)6,7dihydro-

    5H-furo[3,2g]ehromen(6b)wasobtainedasayellowcrystal,yield70.I%,m.P.248—250.C;1R(KBr),9/cm..:2941,1618,1605,l506,1335,1309,1246,l150,1128,1088,992,984,842,834,762;HNMR(300MHz,DMSO-d6),:

    1.96—2.00(m,2H,CH2),2.89(t,2H,CH2),4.24(t,2H,CH2—0),6.76(d,2H,Ar—H,J=8.4Hz),6.98(s,1H,Ar—H),7.25(d,2H,Ar—H,J--8.4Hz),7.35(s,1H,Ar—H),7.43(d,2H,Ar—H./=-8.7Hz),7.75(d,2H,Ar—H,J=8.7Hz).ESI—MS,m/z

    405.1M+H+.Elementalana1.(%)calcd.forC24HI7CIO4:C71.20.H4.23;found:C71.11.H4l30.

    2(4Methylbenzoy1)3-(4-hydroxypheny1)6,7dihydro-

    5H-furo[3,2g]chromen(6c)wasobtainedasayellowcrystal,yield69.3%,m.P.228—23O.C;IR(KBr),9/cm:2935,1613,l597l510,1333,l309,l239,1253,1007,833,776,762;

    HNMR(300MHz,DMSO-d6),:1.98(m,2H,CH2),2.37(s,3H,cH3),2.90(t,2H,CH2),4.23(t,2H,cH2—0),6.75(d,2H,Ar—H,J=8.4Hz),6.98(s,IH,Ar—H),7.22(d,2H,Ar—H,

    卜一J=8.1Hz).7.29(d,2H,Ar—H,J-8.7Hz),7.34(s,1H,AH),

    7.67(d,2HH,8.1Hz).ESI.MS,m/z:385.2M+H

    Elementalana1.(%)calcd.forC25H2oO4:C78.11,H5.24;foundC78.02.H5.10.

    227Svnthesisof2-Aroy13aryl6.7dihvdro5H—

    一翊mrof3.2chromens')

    Compound6(2mmol1wasdissolvedinacetone(20mL)towhichK2CO3(20mmo1)andalkylchloride(2mmo1)wereadded.Thenthemixturewasrefluxedfor8—24huntiltheTLCassayindicatedthatthereactionwascompleted.Thenitwasfilteredandevaporatedtoremovesolvent.Thepurificationoftheresiduebycolumnchromatograph),onsilicawithethyl

    acetateandpetroleumether~ethylacetate):petroleum

    ether)=l:2astheeluentgavecompound7asayellowliquid,whichwasdissolvedinethyletherandventilatedwithhydro.genchloridegastogetprecipitation

    2-Benzoyl-3-{4-2-(4morpholiny1)ethoxyphen-yl}6.7

    dihydro-5H-furo[3,2glchromen(7a1wasobtainedasayellow

    crystal,yield72.5%,m.P.112I14.c;IR(KBr),Wcm:

    2930,l6261600,1554,l506,1335,1309,1243,ll78,l152,ll29,1003,83l,762;HNMR(600MHz,CDCI),:2.04—2.06(m,2H,CH2),2.92(t,2H,CH2),3.08(s.2H,NCH2),3.46(s,

    2H,NCH2),3.57(t,2H,CH2N),4.00(t,2H,OCH2),4.26—

    卜一4.33(m,4H,CH2—0),4.64(s,2H,OCH2),6.94(d,2H,AH,

    ,

    /--8.4Hz),7.02(s,1H,Ar—H),7.30(s,lH,AH),

    7.36—7.40(m,2H,Ar—H),7.47—7.51(m,3H,Ar—H),7.90(d,2H,Ar—H,J=6.6Hz).ESI—Ms,m/z:484.2[M+H].Elemental

    ana1.(%)calcd.forC30H29NO5:C74.52,H6.04,N2.90;found:C74-45,H5.98,N2.85.

    一【2-Benzoyl-3-{42-(1-piperidiny1)eth0xypheny1)-6,7

    dihydro.5furo[3.2.g]chromen(7b)wasobtainedasayellowcrysta1.yield76.9%.m.P.222—224.C:IR(KBr),9/cm:2942163415551506,1333,1308.1244l152,l126,1003,939829738;HNMR(600MHz,CDCl),:1.43—1.48(m,lH,CH2),1.89—1.94(m,3H,CH2),2.O3—2.07(m,2H,CH2),2.28—2.35(m,2H,CH2),2.80—2.85(m,2H,NCH2),2.92(t,2H,

    CH2),3.4O3.41(m,2H,NCHz),3.65—3.67(m,2H,NCH2),

    4.27(t,2H,CH2O),4.62(t,2H,CH2O),6.93(d,2H,AH,

    卜一J=8.4Hz),7.01(s,1H,Ar—H),7.29(s,lH,AH),7I37—7-39

    (m2H.Ar—H1,7.46—7.51(m,2H.Ar—H),7.88—7.90(dd,2H.Ar—H8.41.2Hz).ESI.MS,m/z:482.1+H1.

    Elementalana1.(%)calcd.forC31H31NO4:C77.31,H6.49,N2.91;found:C77-25,H6.56,N2.84.

    2-(4Chlorobenzoy1)3{4-2-(4morpholiny1)ethoxy-

    phenyl}6,7-dihydro-5H-uro[3,2-g]chromen(7c)wasobtainedasayellowcrystal,yield69.2%,m.P.121—123.C:IR(KBr),/cm_.:2930l627,1586,1547,l506,1334,l309,1289,l246,1176l152l1301003,936,830,762;'HNMR(600MHz,CDC13),fi:2.03—2.07(m,2H,CH2),2.92(t,2H,CH2),3.1l(s,2H,NCH2),3.48(s,2H,NCH2),3.59(s,2H,NCH2),4.02(s,2H,OCH2),4.27(t,2H,CH2—0),4-31(s,2H,OCH2),4.67(s,2H,

    0CH,).6.95(d.2H,Ar—H,J--6.6Hz),7.00(s,1H,H),

    728(s,1H,Ar—H),7.35(d,2H,Ar-H,J=8.4Hz),7.46(d,2H,Ar—H,/--7.2Hz17.84(d,2H,Ar—H,J--7.8nz).ESI-MS,m/z:

    5l8-3M+H_.Elementalana1.(%)calcd.forC3oH28CINOs:C69.56,H5.45.N2.70;found:C69.42,H5.40,N2.78.

    2-(4-chlorobenzoy1)-3-{4-2(1-piperidiny1)ethoxy-

    phenyl}-6,7-dihydro-5H-foro[3,2-g]chromen(Td)wasobtMned

    asayellowcrysta1.yield71.5%,m.P.113l14.C;IR(KBr),

    17/cm..:2946.

    1626,1606,l586,1505,1334,1308,1287,l245,1151,11281002,829,762;HNMR(600MHz,CDCI3),:1.44—1.46(m,1H,CH2),1.90—1.92(m,3H,CH2),2.04—2.06(m,2H,cH2),2.31—2.32(m,2H,CH2),2.81—2.83(m,2H,NCH2),2.92(t,2H,CH2),3.43(s,2H,NCH2),3.67(s,2H,

    NCH2),4.27(t,2H,CH2—0),4.63(s,2H,CH2O),6.94(d,2H,

    Ar—H,J=7.2Hz),7.00(s,1H,Ar—H),7.29(s,lH,—H),7.35(d.2H,Ar--H,J=9.0Hz),7.45(d,2H,Ar—H,J=-7.8Hz),

    7.84(d2H,Ar—H,,]--7.8Hz).ESI-MS,m/z:516.2M+H.

    Elcmentalana1.f%)calcd.forC31H30C1NO4:C72.15,H5.86,N2.71:found:C72.10.H5.90N2.66.

    2-(4Methylbenzoy1)3{4-[2-(4-morpholiny1)ethoxy-

    phenyl}-6,7dihydro5H-furo[3,2g]chromen(7e)wasobtained

    asayellowcrysta1.yield73.8%,m.P.1l5l17.C;IR(IO3r),

    P/cm:29301626,1607,l543,l504,l333,l308,1286,1241,l180.1l5l1128l004,830,761;HNMR(600MHz,CDCl3),:2.04—2.06(m,2H,CH2),2.40(s,3H,CH3),2.92(t,2H,CH9,3.10(s,2H,NCH2),3.48(s,2H,NCH2),3.59(s,2H,NCH2),

    4.02(s,2H,OCH2),4.26—4.29(m,4H,CH2O),4.67(s,2H,

    OCH2),6.96(d,2H,Ar—H,J=6.6Hz),7.00(s,1H,H),

    NO.1WANGShi.huietal57

    7.22(d,2H,H,J=7.8nz),7.28(s,1H,Ar—H),7.52(d,2H,Ar—H,J=7.2nz),7.86(d,2H,Ar—H,J=7.8Hz).ESI-MS,

    m/z:498.2M+H+.Elementalana1.(%)calcd.forC31H31N05:C74.83,H6.28,N2.8l;found:C74.76,H6_2O,N2.74.

    一【2-(4-Methylbenzoy1)3-{42-(1-piperidiny1)ethoxy?

    phenyl}-6,7dihydro-5H-furo[3,2glchromen(7f)wasobtainedasayellowcrystal,yield67.3%,m.P.126—128.C;1R(KBr),

    /cm:29441627l608,1505.1384,1334,1309,1245,1180,

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